Transition Metal Sequestration by the Host-Defense Protein Calprotectin.

In response to microbial infection, the human host deploys metal-sequestering host-defense proteins, which reduce nutrient availability and thereby inhibit microbial growth and virulence. Calprotectin (CP) is an abundant antimicrobial protein released from neutrophils and epithelial cells at sites of infection. CP sequesters divalent first-row transition metal ions to limit the availability of essential metal nutrients in the extracellular space. While functional and clinical studies of CP have been pursued for decades, advances in our understanding of its biological coordination chemistry, which is central to its role in the host-microbe interaction, have been made in more recent years. In this review, we focus on the coordination chemistry of CP and highlight studies of its metal-binding properties and contributions to the metal-withholding innate immune response. Taken together, these recent studies inform our current model of how CP participates in metal homeostasis and immunity, and they provide a foundation for further investigations of a remarkable metal-chelating protein at the host-microbe interface and beyond.

PRRX1-fused mesenchymal neoplasm: A novel PRRX1::NCOA1 fusion transcript.

PRRX1-fused mesenchymal neoplasm is a recently identified, rare subcutaneous soft tissue neoplasm that is characterized by fusion of PRRX1 (exon 1) with NCOA1 (exon 13) in the majority of reported cases. Although initially considered to be fibroblastic, a possibility of neural or neuroectodermal differentiation has been suggested in a subset of cases. We report a 26-year-old female with a 4.0 cm painless mass located in the subcutis of the left thigh. Microscopically, the tumor was well-circumscribed and multinodular and was composed of relatively monomorphic ovoid to spindle cells arranged in loose fascicles, trabeculae, and cords within alternating myxoid and fibrous matrix, and vascularized stroma. Mitotic figures were scarce and necrosis was not observed. By immunohistochemistry, the neoplastic cells demonstrated focal co-expression of S100 protein and SOX10 and were negative for epithelial membrane antigen, smooth muscle actin, desmin, CD34, STAT6, HMB45, Melan-A, and MUC4. The expression of Rb1 was retained. Targeted RNA-sequencing identified a novel transcript fusion of PRRX1 (exon 1)::NCOA1 (exon 15), which was further confirmed by reverse transcription polymerase chain reaction and Sanger sequencing. The tumor was narrowly excised and no tumor recurrence or metastasis was identified after 13 months of follow-up. In summary, we report a new case of PRRX1-fused mesenchymal neoplasm, expanding the molecular genetic spectrum and providing further support for possible neural or neuroectodermal differentiation of this emerging soft tissue tumor entity.

Primary schwannoma of the thyroid gland: analysis of case characteristics and review of the literature.

BACKGROUND: To improve the characteristics of primary thyroid schwannomas (PTS) and to provide reference basis for clinical diagnosis and treatment. METHODS: PubMed was searched for case reports of PTS up to December 2022 using the search terms "Thyroid nerve sheath tumor" or "Thyroid schwannoma" or "Thyroid Neurilemmoma", respectively. 34 cases were screened. RESULTS: PTS can occur at any age, nodules averaged 3.9 cm. The most common symptoms were voice change and dysphagia. Fine needle aspiration cytology showing spindle-shaped cells should be considered for schwannoma. Most cases underwent thyroid lobectomy or nodule removal with a good prognosis. Tissue types with both Antoni A and Antoni B features are common. Positive immunohistochemical staining for S-100 protein, CD34 and waveform proteins helped confirm the diagnosis. CONCLUSIONS: Positive immunohistochemistry for S-100 and wave proteins helps confirm the diagnosis. Preoperative diagnosis is challenging, but pathology and immunohistochemical staining are the gold standard for diagnosis. The first choice of treatment is surgical resection of the nodules, the prognosis is good.

FGFR1 gene fusions in a subset of pediatric mesenchymal tumors: Expanding the genetic spectrum of tumors sharing histologic overlap with infantile fibrosarcoma and "NTRK-rearranged" spindle cell neoplasms.

As the classification of kinase-driven spindle cell tumors continues to evolve, we describe the first series of pediatric mesenchymal tumors harboring FGFR1 gene fusions that share histologic overlap with infantile fibrosarcoma and "NTRK-rearranged" spindle cell neoplasms. Herein, we present three cases of FGFR1-rearranged pediatric mesenchymal tumors, including one case with FGFR1::PARD6B gene fusion and two cases with FGFR1::EBF2 gene fusion. The tumors involved infants ranging from 3 to 9 months in age with a male-to-female ratio of 2:1. All tumors involved the deep soft tissue of the gluteal, pelvic, or perirectal region. Histologically, the tumors comprised a cellular spindle cell neoplasm with primitive stellate cells, focal myxoid stroma, focal epithelioid features, no necrosis, and occasional mitotic figures (2-6 per 10 high-power field). By immunohistochemistry, the neoplastic cells focally expressed CD34 but lacked expression of S100 protein, SMA, desmin, myogenin, MyoD1, pan-TRK, and ALK. These three cases, including a case with long-term clinical follow-up, demonstrate that FGFR1 fusions occur in a subset of newly described pediatric kinase-driven mesenchymal tumors with locally aggressive behavior. Importantly, knowledge of these genetic alterations in this spectrum of pediatric tumors is key for diagnostic and targeted therapeutic purposes.

The Role of Serum Calprotectin in Defining Disease Outcomes in Non-Systemic Juvenile Idiopathic Arthritis: A Pilot Study.

Serum calprotectin (MRP8/14) is currently being studied as a promising biomarker of disease activity and outcome in patients with juvenile idiopathic arthritis (JIA) but the data in the literature are conflicting. The aim of our study was to investigate the potential role of serum calprotectin as biomarker of disease activity and flare/remission in a group of nsJIA patients during a follow-up period of 18 months. In this prospective longitudinal study, two groups of patients with ns-JIA (55 active patients and 56 patients in remission according to Wallace's criteria) and a control group (50 children) were recruited at baseline from January 2020 to September 2021. JIA patients were followed for up to 18 months at four timepoints: 3 months (T1), 6 months (T2), 12 months (T3) and 18 months (T4). At each timepoint, the following were recorded: JADAS27, blood counts, ESR, CRP, albumin, ferritin and serum calprotectin. To illustrate the performance of calprotectin, Kaplan-Meier curves were constructed from baseline to relapse/remission, dichotomizing patients at baseline in positive/negative on the basis progressive calprotectin cut-offs. Associations between baseline factors and relapse were determined using Cox regression models. Multivariate models were constructed to analyze the effect of covariates. Comparing baseline clinical and laboratory data of the three groups (active vs. inactive JIA vs. controls), only serum calprotectin reached statistical significance (active patients vs. inactive (p = 0.0016) and vs. controls (p = 0.0012)). In the inactive group, during the 18 months of follow up, 31 patients (55.3%) had a relapse. Comparing the baseline data of relapsers vs. non-relapsers, serum calprotectin showed higher levels (p = 0.001) in relapsers. In survival analysis, a log rank test showed significant differences of up to 12 ng/mL (p = 0.045). Multivariate Cox regression confirmed that only baseline calprotectin levels were independently associated with disease recurrence. In the active group, in the 12 months of follow-up, 19 patients (38%) entered remission of the disease. In addition, in this group, the only statistical difference at the baseline was the value of MPR8/14 (p = 0.0001). Log rank test showed significant differences up to 10 ng/mL (p = 0.003). In the multivariate Cox regression, serum calprotectin levels at baseline were independently associated with remission. In conclusion, our study would suggest a dual role for calprotectin in predicting future relapse and treatment response in patients with nsJIA, thus influencing therapeutic decisions and management of these patients during follow up.

BRAF-rearranged spindle cell mesenchymal neoplasm with a predominant lipofibromatosis-like neural tumor pattern and co-expression of CD34, S100 protein, and markers associated with perineurial differentiation: A rare case with potential diagnostic pitfall.

Recently, a distinctive group of S100 protein/CD34-positive spindle cell mesenchymal neoplasms characterized by a predominant lipofibromatosis-like neural pattern harboring recurrent gene rearrangements involving NTRK1-3, RAF1, RET, ROS1, ALK, and MET has been identified. BRAF rearrangements have been rarely documented in this group of neoplasms. Herein, we report a 54-year-old man with a 1.3-cm painless mass located in the subcutis of left back. The tumor was composed of mildly atypical, short-spindle shaped to ovoid cells with fascicles and whorls intervening between and admixed with the subcutaneous adipose tissues and nerve bundles. Focally abundant thick, band-like stromal hyalinization was also noted. The neoplastic cells showed diffuse reactivity for S100 protein and CD34 and multifocal immunopositivity for markers associated with perineurial differentiation including epithelial membrane antigen, GLUT1, and claudin-1. Fluorescence in situ hybridization analyses showed positive for BRAF rearrangement and negative for rearrangements involving NTRK1, RET, and ROS1. The tumor was narrowly excised and recurred after 24 months of follow-up. To our knowledge, we report the second case of BRAF-rearranged spindle cell mesenchymal tumor with predominant lipofibromatosis-like neural tumor pattern. Expression of markers associated with perineurial differentiation is exceptional and represents a potential diagnostic pitfall, which may cause significant diagnostic confusion with a peripheral nerve sheath tumor.

Calcicoptosis Induced by Purple Sweet Potato Anthocyanins through the Nonosmotic Regulation of the NFAT5/S100A4-S100A9 Pathway in Acute Lymphoblastic Leukemia.

Purple sweet potato is considered an abundant, inexpensive, and ideal source of anthocyanins. Purple sweet potato anthocyanins (PSPAs) have been shown to possess high antimutagenicity and antitumor effects due to the abundance of acylated anthocyanins. However, the effect and underlying mechanism of PSPA effects in acute lymphoblastic leukemia (ALL), especially T-cell acute lymphoblastic leukemia (T-ALL), remain unclear. In this study, the antileukemic effects of PSPAs and the underlying molecular mechanisms were evaluated by in vitro and in silico assays. PSPAs extracted from ten cultivars were analyzed and quantified. Anthocyanins from Nanzi 018, which showed the best antileukemic effect, were selected to analyze the underlying mechanism. First, the PSPAs potently reduced cell viability and induced apoptosis. Additionally, the PSPAs sharply increased intracellular Ca2+ levels, which resulted in calcium overload in T-ALL cells. Furthermore, on the basis of bioinformatics analyses, we focused on an osmotically regulated transcription factor, NFAT5. Molecular docking preliminarily indicated that PSPA molecules bound and interacted with the NFAT5 protein. Western blot analyses confirmed that PSPAs elicited calcium overload by nonosmotic regulation of NFAT5/S100A4-S100A9 pathway activation. Moreover, pretreatment with a NFAT5 inducer confirmed that PSPAs targeted NFAT5 and affected p38/NF-κB/Bcl-2/Caspase-3 axis activation. This study demonstrates that PSPAs exert their antileukemic effects through calcicoptosis induction by targeting NFAT5.

Clinicopathological study of gastric schwannoma and review of related literature.

BACKGROUND: This study aimed to investigate the clinical features, diagnostic criteria, treatment options, and prognosis of patients with gastric schwannoma (GS). METHODS: We collected the clinical data of all patients pathologically diagnosed with GS in Zhejiang Provincial People's Hospital from May 2012 to October 2021. RESULTS: A total of 26 cases of GS were analyzed clinicopathologically, where the sizes of the tumor were found to be in the range of 1-6 cm (mean: 3.16 cm, median: 3.05 cm). A computed tomography (CT) scan analysis revealed that most masses were either moderately progressive or uniformly enhanced. According to ultrasound gastroscopy results, most of them were hypoechoic masses. There were 23 cases of surgery and three cases of endoscopic submucosal tumor dissection. Immunohistochemistry demonstrated that S100 was positive in 26 patients, immunomarker SOX10 was positive in five, whereas CD34, CD117, and SMA were negative in most patients. CK (Pan), Dog-1, and Desmin were also found negative. All 26 cases were followed up after the conclusion of the study where no evidence of recurrence or metastasis was observed. CONCLUSIONS: GS is a unique form of peripheral schwannoma. The diagnosis of this type of tumor depends on the pathology and immunohistochemistry of the individual. The key to treating this type of tumor is endoscopy and surgery. Follow up and related literature review showed that GS was a benign tumor with little possibility of malignant transformation.

Alarmins as a Possible Target of Future Therapies for Atrial Fibrillation.

To date, worldwide, atrial fibrillation is the most common cardiovascular disease in adults, with a prevalence of 2% to 4%. The trigger of the pathophysiological mechanism of arrhythmia includes several factors that sustain and exacerbate the disease. Ectopic electrical conductivity, associated with the resulting atrial mechanical dysfunction, atrial remodeling, and fibrosis, promotes hypo-contractility and blood stasis, involving micro endothelial damage. This causes a significant local inflammatory reaction that feeds and sustains the arrhythmia. In our literature review, we evaluate the role of HMGB1 proteins, heat shock proteins, and S100 in the pathophysiology of atrial fibrillation, offering suggestions for possible new therapeutic strategies. We selected scientific publications on the specific topics "alarmins" and "atrial fibrillation" from PubMed. The nonsystematic review confirms the pivotal role of molecules such as S100 proteins, high-mobility group box-1, and heat shock proteins in the molecular pattern of atrial fibrillation. These results could be considered for new therapeutic opportunities, including inhibition of oxidative stress, evaluation of new anticoagulant drugs with novel therapeutic targets, molecular and genetic studies, and consideration of these alarmins as predictive or prognostic biomarkers of disease onset and severity.

Specific S100 Proteins Bind Tumor Necrosis Factor and Inhibit Its Activity.

Tumor necrosis factor (TNF) inhibitors (anti-TNFs) represent a cornerstone of the treatment of various immune-mediated inflammatory diseases and are among the most commercially successful therapeutic agents. Knowledge of TNF binding partners is critical for identification of the factors able to affect clinical efficacy of the anti-TNFs. Here, we report that among eighteen representatives of the multifunctional S100 protein family, only S100A11, S100A12 and S100A13 interact with the soluble form of TNF (sTNF) in vitro. The lowest equilibrium dissociation constants (Kd) for the complexes with monomeric sTNF determined using surface plasmon resonance spectroscopy range from 2 nM to 28 nM. The apparent Kd values for the complexes of multimeric sTNF with S100A11/A12 estimated from fluorimetric titrations are 0.1-0.3 µM. S100A12/A13 suppress the cytotoxic activity of sTNF against Huh-7 cells, as evidenced by the MTT assay. Structural modeling indicates that the sTNF-S100 interactions may interfere with the sTNF recognition by the therapeutic anti-TNFs. Bioinformatics analysis reveals dysregulation of TNF and S100A11/A12/A13 in numerous disorders. Overall, we have shown a novel potential regulatory role of the extracellular forms of specific S100 proteins that may affect the efficacy of anti-TNF treatment in various diseases.

Calcium-Bound S100P Protein Is a Promiscuous Binding Partner of the Four-Helical Cytokines.

S100 proteins are multifunctional calcium-binding proteins of vertebrates that act intracellularly, extracellularly, or both, and are engaged in the progression of many socially significant diseases. Their extracellular action is typically mediated by the recognition of specific receptor proteins. Recent studies indicate the ability of some S100 proteins to affect cytokine signaling through direct interaction with cytokines. S100P was shown to be the S100 protein most actively involved in interactions with some four-helical cytokines. To assess the selectivity of the S100P protein binding to four-helical cytokines, we have probed the interaction of Ca2+-bound recombinant human S100P with a panel of 32 four-helical human cytokines covering all structural families of this fold, using surface plasmon resonance spectroscopy. A total of 22 cytokines from all families of four-helical cytokines are S100P binders with the equilibrium dissociation constants, Kd, ranging from 1 nM to 3 µM (below the Kd value for the S100P complex with the V domain of its conventional receptor, receptor for advanced glycation end products, RAGE). Molecular docking and mutagenesis studies revealed the presence in the S100P molecule of a cytokine-binding site, which overlaps with the RAGE-binding site. Since S100 binding to four-helical cytokines inhibits their signaling in some cases, the revealed ability of the S100P protein to interact with ca. 71% of the four-helical cytokines indicates that S100P may serve as a poorly selective inhibitor of their action.

The mutation of BCOR is highly recurrent and oncogenic in mature T-cell lymphoma.

BACKGROUND: BCOR acts as a corepressor of BCL6, a potent oncogenic protein in cancers of the lymphoid lineage. We have found the recurrent somatic mutation of BCOR occurred in mature T-cell lymphoma (TCL). The role of BCOR mutation in lymphoid malignancies is unknown. METHODS: Lymphoma patient samples were analyzed to identify missense mutations in BCOR using Sanger sequencing. Transfection, RNA interference, immunoprecipitation, western blotting, cell proliferation, cytokine assays and quantitative real-time PCR were employed to determine the functional relevance of the novel K607E mutation in BCOR. The significant transcriptional changes were analyzed by performing DNA microarray profiling in cells expressing BCOR K607E mutant. RESULTS: One hundred thirty-seven lymphoma patient samples were analyzed to identify K607E mutation of the BCOR gene. The BCOR K607E mutation was identified in 15 of 47 NK/T cell lymphoma cases (31.9%), 2 of 18 angioimmunoblastic T-cell lymphoma cases (11.1%), 10 of 30 peripheral T-cell lymphoma, not otherwise specified cases (33.3%), and 13 of 42 diffuse large B-cell lymphoma cases (30.9%). Molecular analysis of BCOR K607E mutation revealed that compared to the wild-type BCOR, the mutant BCOR bound to the BCL6, PCGF1, and RING1B proteins with lesser affinity. Ectopic expression of BCOR K607E mutant significantly enhanced cell proliferation, AKT phosphorylation and the expression of interleukin-2 (IL-2) with up-regulated expression of HOX and S100 protein genes in T cells. BCOR silencing also significantly enhanced cell proliferation, AKT phosphorylation, and IL-2 production. CONCLUSIONS: Functional analyses indicated that K607E mutation of BCOR is oncogenic in nature and can serve as a genetic marker of T-cell lymphoma.

Localization of Neurotrophin Specific Trk Receptors in Mechanosensory Systems of Killifish (Nothobranchius guentheri).

Neurotrophins (NTs) and their signal-transducing Trk receptors play a crucial role in the development and maintenance of specific neuronal subpopulations in nervous and sensory systems. NTs are supposed to regulate two sensory systems in fish, the inner ear and the lateral line system (LLS). The latter is one of the major mechanosensory systems in fish. Considering that annual fishes of the genus Nothobranchius, with their short life expectancy, have become a suitable model for aging studies and that the occurrence and distribution of neurotrophin Trk receptors have never been investigated in the inner ear and LLS of killifish (Nothobranchius guentheri), our study aimed to investigate the localization of neurotrophin-specific Trk receptors in mechanosensory systems of N. guentheri. For histological and immunohistochemical analysis, adult specimens of N. guentheri were processed using antibodies against Trk receptors and S100 protein. An intense immunoreaction for TrkA and TrkC was found in the sensory cells of the inner ear as well as in the hair cells of LLS. Moreover, also the neurons localized in the acoustic ganglia displayed a specific immunoreaction for all Trk receptors (TrkA, B, and C) analyzed. Taken together, our results demonstrate, for the first time, that neurotrophins and their specific receptors could play a pivotal role in the biology of the sensory cells of the inner ear and LLS of N. guentheri and might also be involved in the hair cells regeneration process in normal and aged conditions.

Immunohistochemical analysis of 36 cases of chondroblastomas: A single institutional experience.

Chondroblastoma is a relatively uncommon, primary benign bone tumor, frequently identified in young individuals. Despite its classical radiologic and histopathological features, at times, it is fraught with a diagnostic challenge, especially differentiating it from a giant cell tumor of bone (GCTB); an osteosarcoma and a chondrosarcoma. Lately, few studies have shown the diagnostic utility of immunohistochemical (IHC) expression DOG1 antibody in chondroblastomas. The present study was undertaken to evaluate IHC expression of S100 protein, DOG1 and p63 in 36 chondroblastomas. From January 2013 to July 2019 (6-year duration), 106 chondroblastomas were diagnosed, with IHC staining performed in 36 cases. Conventional Hematoxylin and Eosin stained microsections and IHC stained sections were reviewed in 36 cases. IHC staining of p63 (intranuclear), S100 protein (nuclear and cytoplasmic) and DOG1 (cytoplasmic membranous) was recorded in various cases. Seventy-four tumors occurred in males and 32 in females, within age-range of 7-55 years (average = 18.6), frequently in tibia (33/106; 31.1%), followed by femur (26, 24.5%) humerus (22, 20.7%), calcaneum (5) and scapula (4). IHC staining for S100P was positive in 33/36cases (91.7%); DOG1 in 16/19 (84.2%) cases and p63 in 10/15cases (66.6%). DOG1 immunostaining was negative in 25 various other tumors. Sensitivity and specificity for S100P, DOG1and p63 in chondroblastomas was (91.6%, 59.3%); (84.2%, 100%) and (66.6%, 46.6%), respectively. P63 was positively expressed in 15/27 (55.5%) GCTBs. S100 protein and DOG1 can be utilized for a confirmatory diagnosis of a chondroblastoma, especially for differentiating it from its other differentials, such as GCTB, in view of certain associated therapeutic implications. P63 is not useful in that scenario.

Interferon Beta Activity Is Modulated via Binding of Specific S100 Proteins.

Interferon-ß (IFN-ß) is a pleiotropic cytokine used for therapy of multiple sclerosis, which is also effective in suppression of viral and bacterial infections and cancer. Recently, we reported a highly specific interaction between IFN-ß and S100P lowering IFN-ß cytotoxicity to cancer cells (Int J Biol Macromol. 2020; 143: 633-639). S100P is a member of large family of multifunctional Ca2+-binding proteins with cytokine-like activities. To probe selectivity of IFN-ß-S100 interaction with respect to S100 proteins, we used surface plasmon resonance spectroscopy, chemical crosslinking, and crystal violet assay. Among the thirteen S100 proteins studied S100A1, S100A4, and S100A6 proteins exhibit strictly Ca2+-dependent binding to IFN-ß with equilibrium dissociation constants, Kd, of 0.04-1.5 µM for their Ca2+-bound homodimeric forms. Calcium depletion abolishes the S100-IFN-ß interactions. Monomerization of S100A1/A4/A6 decreases Kd values down to 0.11-1.0 nM. Interferon-α is unable of binding to the S100 proteins studied. S100A1/A4 proteins inhibit IFN-ß-induced suppression of MCF-7 cells viability. The revealed direct influence of specific S100 proteins on IFN-ß activity uncovers a novel regulatory role of particular S100 proteins, and opens up novel approaches to enhancement of therapeutic efficacy of IFN-ß.

Zooming into the Dark Side of Human Annexin-S100 Complexes: Dynamic Alliance of Flexible Partners.

Annexins and S100 proteins form two large families of Ca2+-binding proteins. They are quite different both structurally and functionally, with S100 proteins being small (10-12 kDa) acidic regulatory proteins from the EF-hand superfamily of Ca2+-binding proteins, and with annexins being at least three-fold larger (329 ± 12 versus 98 ± 7 residues) and using non-EF-hand-based mechanism for calcium binding. Members of both families have multiple biological roles, being able to bind to a large cohort of partners and possessing a multitude of functions. Furthermore, annexins and S100 proteins can interact with each other in either a Ca2+-dependent or Ca2+-independent manner, forming functional annexin-S100 complexes. Such functional polymorphism and binding indiscrimination are rather unexpected, since structural information is available for many annexins and S100 proteins, which therefore are considered as ordered proteins that should follow the classical "one protein-one structure-one function" model. On the other hand, the ability to be engaged in a wide range of interactions with multiple, often unrelated, binding partners and possess multiple functions represent characteristic features of intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs); i.e., functional proteins or protein regions lacking unique tertiary structures. The aim of this paper is to provide an overview of the functional roles of human annexins and S100 proteins, and to use the protein intrinsic disorder perspective to explain their exceptional multifunctionality and binding promiscuity.

Non-Neural (S-100 Negative) Bronchial Granular Cell Tumor Causing Acute Respiratory Failure.

Introduction: Endobronchial granular cell tumors are uncommon in the pediatric population. Case report: A 9-year-old female presented with respiratory failure due to an endobronchial tumor. After debulking and diagnosis, she underwent thoracotomy with right upper lobe resection and bronchoplasty. Pathology demonstrated an endobronchial S-100 negative granular cell tumor, which to our knowledge, is the first such report in the literature. Conclusion: Endobronchial granular cell tumors may cause obstructive respiratory failure, are amenable to surgery, and may be S-100 negative.

Multiple S100 protein isoforms and C-terminal phosphorylation contribute to the paralog-selective regulation of nonmuscle myosin 2 filaments.

Nonmuscle myosin 2 (NM2) has three paralogs in mammals, NM2A, NM2B, and NM2C, which have both unique and overlapping functions in cell migration, formation of cell-cell adhesions, and cell polarity. Their assembly into homo- and heterotypic bipolar filaments in living cells is primarily regulated by phosphorylation of the N-terminally bound regulatory light chain. Here, we present evidence that the equilibrium between these filaments and single NM2A and NM2B molecules can be controlled via S100 calcium-binding protein interactions and phosphorylation at the C-terminal end of the heavy chains. Furthermore, we show that in addition to S100A4, other members of the S100 family can also mediate disassembly of homotypic NM2A filaments. Importantly, these proteins can selectively remove NM2A molecules from heterotypic filaments. We also found that tail phosphorylation (at Ser-1956 and Ser-1975) of NM2B by casein kinase 2, as well as phosphomimetic substitutions at sites targeted by protein kinase C (PKC) and transient receptor potential cation channel subfamily M member 7 (TRPM7), down-regulates filament assembly in an additive fashion. Tail phosphorylation of NM2A had a comparatively minor effect on filament stability. S100 binding and tail phosphorylation therefore preferentially disassemble NM2A and NM2B, respectively. These two distinct mechanisms are likely to contribute to the temporal and spatial sorting of the two NM2 paralogs within heterotypic filaments. The existence of multiple NM2A-depolymerizing S100 paralogs offers the potential for diverse regulatory inputs modulating NM2A filament disassembly in cells and provides functional redundancy under both physiological and pathological conditions.

Neuroplastin-ß mediates S100A8/A9-induced lung cancer disseminative progression.

Compiling evidence indicates an unusual role of extracellular S100A8/A9 in cancer metastasis. S100A8/A9 secreted from either cancer cells or normal cells including epithelial and inflammatory cells stimulates cancer cells through S100A8/A9 sensor receptors in an autocrine or paracrine manner, leading to cancer cell metastatic progression. We previously reported a novel S100A8/A9 receptor, neuroplastin-ß (NPTNß), which plays a critical role in atopic dermatitis when it is highly activated in keratinocytes by an excess amount of extracellular S100A8/A9 in the inflammatory skin lesion. Interestingly, our expression profiling of NPTNß showed significantly high expression levels in lung cancer cell lines in a consistent manner. We hence aimed to determine the significance of NPTNß as an S100A8/A9 receptor in lung cancer. Our results showed that NPTNß has strong ability to induce cancer-related cellular events, including anchorage-independent growth, motility and invasiveness, in lung cancer cells in response to extracellular S100A8/A9, eventually leading to the expression of a cancer disseminative phenotype in lung tissue in vivo. Mechanistic investigation revealed that binding of S100A8/A9 to NPTNß mediates activation of NFIA and NFIB and following SPDEF transcription factors through orchestrated upstream signals from TRAF2 and RAS, which is linked to anchorage-independent growth, motility and invasiveness. Overall, our results indicate the importance of the S100A8/A9-NPTNß axis in lung cancer disseminative progression and reveal a pivotal role of its newly identified downstream signaling, TRAF2/RAS-NFIA/NFIB-SPDEF, in linking to the aggressive development of lung cancers.

Characterization of the fish ovarian stroma during the spawning season: Cytochemical, immunohistochemical and ultrastructural studies.

The changes in the ovarian stroma of the fish during their spawning season become it an excellent biological model for studies on cellular and vascular elements due to the intense tissue remodeling in fish occur naturally throughout this critical period. The present study aims to investigate the cellular and vascular components of the ovarian stroma of Redbelly tilapia during the spawning season by conventional, immunohistochemical stains as well as to detect the ultrastructural characteristics for each stromal component. The histological examinations revealed a series of blood vessels with special structures, include throttle artery, glomus, spirally oriented arterioles, modified arteries, and veins as well as arteriovenous anastomosis. Various types of cells were detected in the stroma include; telocytes, rodlet cells, mast cells, eosinophils, neutrophils, lymphocytes, fibroblasts, macrophages, melanocytes, adipocytes, dendritic cells, and endocrine (steroidogenic, interstitial) cells. Moreover, these stromal cells showed a broad range of staining affinity against c-kit, desmin, and s100-protein. Bundles of nerve fibers were detected between the follicles. This study exposed various cellular and vascular components with distinct functions in the ovary of Redbelly tilapia during the spawning season.